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A new variant translocation 11;17 in a patient with acute promyelocytic leukemia together with t(7;12)
A New Variant Translocation 11;17 in a Patient with Acute Promyelocytic Leukemia Together with t(7;12) Vesna Najfeld, Angela Scalise, and Kevin Troy
ABSTRACT: Bone marrow cells from the majority of patients with acute promyelocytic leukemia (APL) are characterized by t(15;17)(q22;q11-12). At least 12 variant translocations have been also reported, and in each case, either abnormal chromosome 15 or del(17q) or both were involved in complex rearrangements. We report a patient with APL showing two translocations without apparent involvement of chromosome 15 and without del(17q). "/'he karyotype was 46,XY,t(7;12)(pl 5;p13),t(11 ;17)(q13;q12). Rearrangement involving t(11;17) is probably associated with APL, while t(7;12) appears to be therapy related. INTRODUCTION The characteristic chromosomal rearrangement found in marrow cells from patients with acute p r o m y e l o c y t i c leukemia (APL) is t(15;17). The breakpoints in this translocation were first placed at 17q21 [1]. In 1984, however, the breakpoint was interpreted to be more p r o x i m a l l y at 17q12 [2]. Finally, at the Ninth Workshop of H u m a n Gene M a p p i n g (HGM9) the participants agreed that the breakpoints in t(15;17) are (q22;q11-12) [3]. The incidence of t(15;17) in APL is between 64% and 100% if marrow and blood cells are cultured prior to the chromosome preparation [4, 5]. At least 12 variant translocations have been described as well as c o m p l e x threeway rearrangements [6-12]. In at least four reported cases, chromosome 15 d i d not a p p e a r to be involved [6-8], and del(17q) was not detected in a few other cases [9, 12]. We report a patient with typical APL showing two different translocations without a p p a r e n t involvement of chromosome 15 and without the formation of del(17q). The karyotype was 46,XY,t(7;12)(p15;p13),t(11;17)(q13;q12). MATERIALS AND METHODS Case Report
M. F. was a 74-year-old white male who first presented in October 1985 with a deep venous thrombosis of the right leg. His complete blood count (CBC) showed a white From the Tumor Cytogenetics Laboratory, Polly Annenberg Levee Hematology Center, Mount Sinai Medical Center, New York, New York.
Address reprint requests to: Vesna Naffeld, Ph.D., Box 1079, Tumor Cytogenetics, Polly Annenberg Levee Hematology Center, Mount Sinai Medical Center, 99th Street and Madison Avenue, New York, NY 10029. Received February 24, 1989; accepted May 16, 1989.
103 C 1989 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cyiogenet43:103-108 (1989) 0165-4608/89/$03.50
104
V. Najfeld et al. blood cell count (WBC) of 17.3 x 10g/L with 74% blasts, a hemoglobin of 14.5 g/dl, and a platelet count of 144 x 109/L. His coagulation profile was compatible with disseminated intravascular coagulation. Bone marrow aspirate showed a hypercellular marrow containing 80% blasts that were devoid of granules and were 97% peroxidase and Sudan Black B (SBB) positive. This picture was suggestive of variant APL. The patient was treated with cytosine arabinoside (ara-C) and daunorubicin and entered remission. He received maintenance therapy with ara-C and thioguanine. He had a bone marrow relapse in May 1986. The bone marrow aspirate at that time revealed 19% blasts and 66% abnormal promyelocytes. Eighty-nine percent of cells were myeloperoxidase positive. He was treated with ara-C and daunorubicin and again entered remission. In November 1986, he relapsed and was again treated with ara-C and daunorubicin. In February 1987 he presented with bone marrow and central nervous system (CNS) relapse and was treated with intrathecal ara-C and systemic chemotherapy consisting of ara-C and mitoxantrone (DHAD). In July 1987 he presented with recurrent CNS leukemia and was treated with intrathecal ara-C and MTX. In August 1987, however, he returned in bone marrow relapse. He was treated with ara-C and thioguanine but failed to respond, and he expired in September 1987.
Cytogenetic Analysis Bone marrow and peripheral blood cells were cultured for 24 hours before they were processed for chromosome studies as described [13].
Cytochemical Stains Cytochemical studies, including stains for myeloperoxidase, SBB, periodic acidSchiff, alpha-naphthyl butyrate esterase, and terminal deoxynucleotidyl transferase (Tdt) were performed on peripheral blood and bone marrow using standard techniques. RESULTS Morphologic and cytochemical studies of marrow and blood cells during the course of the disease combined with the occurrence of disseminated intravascular coagulation (DIC) at presentation are consistent with a diagnosis of APL-M3. Chromosome analyses of marrow cells were performed at diagnosis (10/8/85), at first relapse on 5/8/ 86, and during the third relapse on 2/17/87. Cytogenetic testing of unstimulated peripheral blood cells was performed on 9/3/87, when the patient was in the fourth relapse. All four preparations were inadequate despite the culture of 24 hours. In contrast, of the 35 analyzed marrow cells from a specimen obtained on 7/20/87, a month before his fourth clinical relapse, seven cells were normal 46,XY, and 28 cells showed an abnormal cell population with two distinct karyotypic rearrangements. The first translocation involved the short arms of chromosomes 7 and 12, and the second rearrangement was between the long arms of chromosomes 11 and 17 (Fig. 1). The karyotype of the relapsed marrow cells was 46,XY,tC7;12)(plS;p13), t(11;17)(q13;q12). Both chromosomes 15 appeared structurally normal, and the loss of genetic material from 17q could not be detected (Fig. 2). DISCUSSION At presentation, this patient's clinical picture was consistent with variant promyelocytic leukemia. His marrow morphology at first relapse was characteristic of typical APL. Cytogenetic analysis of marrow cells at diagnosis was not successful, hut a
t(11;17) and t(7;12 in APL
1
105
2
3
6
7
8
13
14
15
F ~t 19
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Figure I A bone marrow karyotype showing two different translocations: t(7;12) and t(11;17). Arrows indicate abnormal chromosome.
chromosomally abnormal clone was detected in marrow cells 1 month prior to the fourth relapse. The possibility that the chromosomally abnormal clone was therapy related cannot be excluded. However, cytogenetic analysis in five of seven reported patients during relapse of APL whose cytogenetic study was inadequate at diagnosis, as in our patient, demonstrated t(15;17) without additional abnormalities [4, 14]. Although t(11;17) was observed after therapy, it is likely, as in cases with t(15;17), that it is not therapy related but rather is associated with APL. In patients with t(15;17)(q22;q11.2), part of chromosome 17 is translocated to the chromosome 15, giving rise to the formations of 15q+ and 17q- chromosomes. In two variant translocations reported thus far, which involved chromosome 15 and left chromosome 17 intact, part of chromosome X and part of chromosome 3, respectively, were both deleted, giving rise in both patients to a 15q+ chromosome [9, 12]. In most of the published cases with involvement of chromosome 17 in the form of a variant translocation, del(17q) or i(17q-), it is the breakpoint on 17q that has been interpreted as more important than the 15q changes in APL development [6]. Our patient represents a rare case of a variant translocation with an apparently intact chromosome 15 and most likely without any loss of genetic material from 17q; the breakpoint on #17 appears to be similar to a typical t(15;17). Furthermore, it is also the first case with APL and a rearrangement involving chromosomes 11 and 17.
106
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Figure 2 A partial karyotype from four marrow cells showing only abnormal chromosomes: t(7;12)(plS;p13) and t(11;17)(q13;q12).
The myeloperoxidase (MPO) gene has been mapped and localized to either 17q2224 [15], 17q12-q21 [16], or 17q22-23 [17]. Using in situ hybridization technique, two groups of investigators documented that MPO is translocated from chromosome 17 to 15q+ in five of eight studied patients with t(15;17) [15, 16]. Furthermore, rearrangements of MPO in two of four studied patients were described [16]. Based on these preliminary molecular studies and on rare variant chromosomal translocations, Weil et al. concluded that 15q+ is the critical recombinant chromosome [16]. Chromosomal localization of another gene, colony-stimulating factor (G-CSF), that promotes growth, differentiation and survival of neutrophilic granulocytes was recently mapped to the two close regions 17qll [18] and 17q11.2-21 [19]. Using in situ hybridization techniques, it has been shown that G-CSF remains on del(17q) and that the G-CSF coding sequence is not disturbed by t(15;17) [18, 19]. From these limited data it was concluded that t(15;17) apparently does not involve the G-CSF sequence, and again that 15q+ chromosome contains the critical function involved in APL pathogenesis. Six other genes have been localized in the region of APL translocations, and altogether seven of eight genes have been reported to be in the germ-line configuration in the typical t(15;17) [20]. Our patient had what appears to be an intact chromosome 15, and del(17q) could not be documented. Lack of involvement of chromosome 15 was documented in four
t(11;17) and t(7;12) in APL
107
patients [6-8]. Thus, either some of the changes on chromosome 15 are below cytogenetic resolution and, therefore, could not be detected, or other interpretations about APL pathogenesis are leasable in view of the fact that some patients with APL do not have involvement of c h r o m o s o m e 15. Our data are consistent with Yamada et al. that the recombinant c h r o m o s o m e 17 is a more critical chromosome and the position effect of one or more genes on 17q÷ (as in our patient) may be one of the explanations for the pathogenesis of APL [6]. But because both chromosomes 15 and 17 have been found intact in some cases of APL, either both play a role, or one or the other recombinant c h r o m o s o m e produces molecular events that can cause maturation arrest at the p r o m y e l o c y t e stage. This variant t(11;17) may be considered analogous either to the " m a s k e d " or complex Philadelphia (Ph) translocations without cytogenetic evidence of # 9 involvement in Ph-positive chronic myelogenous leukemia (CML) or to some variant translocations in Ph-negative CML without cytogenetic involvement of chromosomes 9 and 22, such as those recently described [21]. In some of these patients there is a formation of hybrid BCR-ABL gene and abnormal mRNA without cytogenetic evidence of the Ph chromosome [21, 22]. One may speculate that in a variant t(11;17) there might have been an exchange on a molecular level of genetic material with chromosome 15, even though chromosome 15 appears cytogenetically intact. The role of chromosome 15 in these rare variants remains speculative, and the juxtapositions of genes on both 15q and 17q in the pathogenesis of APL still needs further elucidation. A second abnormality observed in marrow cells of our patient was t(7;12) (p15;p12). This specific rearrangement has been d o c u m e n t e d in only one reported patient with acute n o n l y m p h o c y t i c leukemia (ANLL] [23]. Another similar reported case had a different breakpoint, at 7p13 [24]. Abnormality of c h r o m o s o m e 7, either in the form of del(7q), m o n o s o m y 7, or inv(Tq) have been frequently reported in APL [4, 18]. But in each case, the involvement of the long arms of chromosome 7 was documented. Therefore, involvements of 7p and 12p have been very rarely reported in ANLL. Two patients with t(7;12) as well as our patient received therapy prior to the c h r o m o s o m e analysis Thus, it may appear that t(7;12)(p15;p13) may be therapy related, rather than arising de novo, and may represent yet another, although rare, marker for treated patients. Therefore it is conceivable that t(7;12) was a secondary change to the primary t(11;17), which we suspect is associated with APL. In summary, a new variant translocation, t(11;17), was detected in relapsed marrow cells from a patient with APL. This translocation was probably a primary change in neoplastic cells. The other translocation, t(7;12), is most likely a secondary change and may represent a rare, n o n r a n d o m abnormality related to treatment. REFERENCES 1. Rowley JD, Golomb HM, Vardiman J, Fukuhara S, Dougherty C, Potter D (1977): Further evidence for a non-random chromosomal abnormality in acute promyelocytic leukemia. Int J Cancer 20:869-672. 2. Fourth International Workshop on Chromosomes in Leukemia, 1962. Chromosomes in acute promyelocytic leukemia (1964): Cancer Genet Cyiogenet 11:286-293. 3. Bloomfield CD, Trent JM, van Den Berghe (1967): Report of the committee on structural chromosome changes in neoplasia. Ninth International Workshop on Human Gene Mapping. (Paris Conference). Cytogenetics and Cell Genetics 46, Nos. 1-4, 344-369. 4. Larson RA, Kondo K, Vardiman JW, Butler AE, Golomb HM, Rowley JD (1984): Evidence for a 15:17 translocation in every patient with acute promyelocytic leukemia. Am J Med 76:627-641. 5. De Braekeleer M (1966): The occurrence of translocation (15;17) in acute promyelocytic leukemia: An update. Cancer Genet Cytogenet 23:275-277. 6. Yamada K, Sugimoto E, Amano M, Imamura Y, Kubota T, Matsumoto M (1963): Two cases
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7.
8. 9. 10. 11.
12.
13. 14.
15.
16.
17.
18.
19.
20.
21.
22. 23. 24.
of acute promyelocytic leukemia with variant translocations: The importance of chromosome No. 17 abnormality. Cancer Genet Cytogenet 9:93-99. Sonoda Y, Misawa S, Maekawa T, Taniwaki M, Abe T, Takino T (1985): A variant 15;17 translocation in a patient with acute promyelocytic leukemia. Cancer Genet Cytogenet 17:61-67. Schwartz JG, Clare N, Hansen K, Britton H, Manhoff L (1986): Acute promyelocytic leukemia: Report of a variant translocation, t(1;17). Cancer Genet Cytogenet 20:89-93. Helm S, Kristoffersson V, Mandahl N, Maim C, Mitelman F: (1988): Variant translocation t(3;15)(q21;q22) in a patient with acute promyelocytic leukemia. Leukemia 2:65-67. Callem DF, Dale BM, Sagere, Ford JH (1985): A complex translocation in acute promyelocytic leukemia. Cancer Genet Cytogenet 16:45-48. Bernstein R, Mendolow B, Pinto MR, Marcom G, Bezwoda W (1980): Complex translocations involving chromosomes 15 and 17 in acute promyelocytic leukemia. Br J Haematol 46:311-314. Srivastava A, Heerema N, Laver RC, Nahreini PH, Boswell HS, Hoffman R and Antony AC (1987): A variant t(X;15)(p11;q22] translocation in acute promyelocytic leukemia. Cancer Genet Cytogenet 29:65-74. Coyle T, Najfeld V (1988): Translocation (3;21) in Philadelphia chromosome-positive chronic myelogenous leukemia prior to the onset of blast crisis. Am J Haematol 27:56-59. Swansbury GJ, Feary SW, Clink H McD, Lawler SD (1985): Cytogenetics of acute promyelocytic leukemia: Incidence of t(15;17) of the Royal Marsden Hospital, London. Leuk Res 9:271-278. Chang KS, Schroeder W, Siciliano MJ, Thompson LH, McCredie K, Beran M, Freireich EJ, Liang JC, Trujillo JM, Stass SA (1987): The localization of the human myeloperoxidase gene is in close proximity to the translocation breakpoint in acute promyelocytic leukemia. Leukemia 1:458-462. Weil SC, Rosner GL, Reid MS, Chisholm RL, Lemons RS, Swanson MS, Carrino JJ, Diaz MO, Le Beau MM (1988): Translocation and rearrangement of myeloperoxidase gene in acute promyelocytic leukemia. Science 240:749-792. van Tuinen P, Johnson KR, Ledbetter SA, Nusbaum RL, Rovera G, Ledbetter DH (1987): Localization of myeloperoxidase to the long arm of human chromosome 17: relationship to the 15;17 translocation of acute promyelocytic leukemia. Oncogene 1:19-22. Le Beau MM, Lemons RS, Carrino JJ, Pettenati MJ, Souza LM, Diaz MO, Rowley JD (1987): Chromosomal localization of the human G-CSF gene to 17qll proximal to the breakpoint of the t(15;17) in acute promyelocytic leukemia. Leukemia 1:795-799. Simmers RN, Webber LM, Shannon MF, Garson OM, Wong G, Vadas MA, Sutherland GR (1987): Localization of the G-CSF gene on chromosome 17 proximal to the breakpoint in the t(15;17) in acute promyelocytic leukemia. Blood 70:330-332. Shaw D, Eiberg H (1987): Report of the Committee for chromosomes 17, 18 and 19. Human Gene Mapping 9. Paris Conference (1987). Cytogenetics and Cell Genetics. 46:Nos. 1-4, 242-256. Van der Plas DC, Hermans ABC, Soelarman D, Smith EME, de Klein A, Smadja N, Alimena G, Goudsmith R, Grosveld G, Hagemeijer A (1989): Cytogenetic and molecular analysis in Philadelphia negative CML. Blood 73:1038-1044. Bartram CR (1988): Rearrangement of the c-abl and bcr genes in Ph-negative CML and Phpositive acute leukemias. Leukemia 2:63-64. Arthur DC, Bloomfield CD (1984): Banded chromosome analysis in patients with treatmentassociated acute nonlymphocytic leukemia. Cancer Genet Cytogenet 12:189-199. Nacheva E, Fischer P, Haas O, Manolova Y, Hanolov G, Levan A (1982): Acute myelogenous leukemia in child with primary involvement.of chromosomes 11 and X. Hereditas 97:273288.
ABSTRACT: Bone marrow cells from the majority of patients with acute promyelocytic leukemia (APL) are characterized by t(15;17)(q22;q11-12). At least 12 variant translocations have been also reported, and in each case, either abnormal chromosome 15 or del(17q) or both were involved in complex rearrangements. We report a patient with APL showing two translocations without apparent involvement of chromosome 15 and without del(17q). "/'he karyotype was 46,XY,t(7;12)(pl 5;p13),t(11 ;17)(q13;q12). Rearrangement involving t(11;17) is probably associated with APL, while t(7;12) appears to be therapy related. INTRODUCTION The characteristic chromosomal rearrangement found in marrow cells from patients with acute p r o m y e l o c y t i c leukemia (APL) is t(15;17). The breakpoints in this translocation were first placed at 17q21 [1]. In 1984, however, the breakpoint was interpreted to be more p r o x i m a l l y at 17q12 [2]. Finally, at the Ninth Workshop of H u m a n Gene M a p p i n g (HGM9) the participants agreed that the breakpoints in t(15;17) are (q22;q11-12) [3]. The incidence of t(15;17) in APL is between 64% and 100% if marrow and blood cells are cultured prior to the chromosome preparation [4, 5]. At least 12 variant translocations have been described as well as c o m p l e x threeway rearrangements [6-12]. In at least four reported cases, chromosome 15 d i d not a p p e a r to be involved [6-8], and del(17q) was not detected in a few other cases [9, 12]. We report a patient with typical APL showing two different translocations without a p p a r e n t involvement of chromosome 15 and without the formation of del(17q). The karyotype was 46,XY,t(7;12)(p15;p13),t(11;17)(q13;q12). MATERIALS AND METHODS Case Report
M. F. was a 74-year-old white male who first presented in October 1985 with a deep venous thrombosis of the right leg. His complete blood count (CBC) showed a white From the Tumor Cytogenetics Laboratory, Polly Annenberg Levee Hematology Center, Mount Sinai Medical Center, New York, New York.
Address reprint requests to: Vesna Naffeld, Ph.D., Box 1079, Tumor Cytogenetics, Polly Annenberg Levee Hematology Center, Mount Sinai Medical Center, 99th Street and Madison Avenue, New York, NY 10029. Received February 24, 1989; accepted May 16, 1989.
103 C 1989 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cyiogenet43:103-108 (1989) 0165-4608/89/$03.50
104
V. Najfeld et al. blood cell count (WBC) of 17.3 x 10g/L with 74% blasts, a hemoglobin of 14.5 g/dl, and a platelet count of 144 x 109/L. His coagulation profile was compatible with disseminated intravascular coagulation. Bone marrow aspirate showed a hypercellular marrow containing 80% blasts that were devoid of granules and were 97% peroxidase and Sudan Black B (SBB) positive. This picture was suggestive of variant APL. The patient was treated with cytosine arabinoside (ara-C) and daunorubicin and entered remission. He received maintenance therapy with ara-C and thioguanine. He had a bone marrow relapse in May 1986. The bone marrow aspirate at that time revealed 19% blasts and 66% abnormal promyelocytes. Eighty-nine percent of cells were myeloperoxidase positive. He was treated with ara-C and daunorubicin and again entered remission. In November 1986, he relapsed and was again treated with ara-C and daunorubicin. In February 1987 he presented with bone marrow and central nervous system (CNS) relapse and was treated with intrathecal ara-C and systemic chemotherapy consisting of ara-C and mitoxantrone (DHAD). In July 1987 he presented with recurrent CNS leukemia and was treated with intrathecal ara-C and MTX. In August 1987, however, he returned in bone marrow relapse. He was treated with ara-C and thioguanine but failed to respond, and he expired in September 1987.
Cytogenetic Analysis Bone marrow and peripheral blood cells were cultured for 24 hours before they were processed for chromosome studies as described [13].
Cytochemical Stains Cytochemical studies, including stains for myeloperoxidase, SBB, periodic acidSchiff, alpha-naphthyl butyrate esterase, and terminal deoxynucleotidyl transferase (Tdt) were performed on peripheral blood and bone marrow using standard techniques. RESULTS Morphologic and cytochemical studies of marrow and blood cells during the course of the disease combined with the occurrence of disseminated intravascular coagulation (DIC) at presentation are consistent with a diagnosis of APL-M3. Chromosome analyses of marrow cells were performed at diagnosis (10/8/85), at first relapse on 5/8/ 86, and during the third relapse on 2/17/87. Cytogenetic testing of unstimulated peripheral blood cells was performed on 9/3/87, when the patient was in the fourth relapse. All four preparations were inadequate despite the culture of 24 hours. In contrast, of the 35 analyzed marrow cells from a specimen obtained on 7/20/87, a month before his fourth clinical relapse, seven cells were normal 46,XY, and 28 cells showed an abnormal cell population with two distinct karyotypic rearrangements. The first translocation involved the short arms of chromosomes 7 and 12, and the second rearrangement was between the long arms of chromosomes 11 and 17 (Fig. 1). The karyotype of the relapsed marrow cells was 46,XY,tC7;12)(plS;p13), t(11;17)(q13;q12). Both chromosomes 15 appeared structurally normal, and the loss of genetic material from 17q could not be detected (Fig. 2). DISCUSSION At presentation, this patient's clinical picture was consistent with variant promyelocytic leukemia. His marrow morphology at first relapse was characteristic of typical APL. Cytogenetic analysis of marrow cells at diagnosis was not successful, hut a
t(11;17) and t(7;12 in APL
1
105
2
3
6
7
8
13
14
15
F ~t 19
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11
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Figure I A bone marrow karyotype showing two different translocations: t(7;12) and t(11;17). Arrows indicate abnormal chromosome.
chromosomally abnormal clone was detected in marrow cells 1 month prior to the fourth relapse. The possibility that the chromosomally abnormal clone was therapy related cannot be excluded. However, cytogenetic analysis in five of seven reported patients during relapse of APL whose cytogenetic study was inadequate at diagnosis, as in our patient, demonstrated t(15;17) without additional abnormalities [4, 14]. Although t(11;17) was observed after therapy, it is likely, as in cases with t(15;17), that it is not therapy related but rather is associated with APL. In patients with t(15;17)(q22;q11.2), part of chromosome 17 is translocated to the chromosome 15, giving rise to the formations of 15q+ and 17q- chromosomes. In two variant translocations reported thus far, which involved chromosome 15 and left chromosome 17 intact, part of chromosome X and part of chromosome 3, respectively, were both deleted, giving rise in both patients to a 15q+ chromosome [9, 12]. In most of the published cases with involvement of chromosome 17 in the form of a variant translocation, del(17q) or i(17q-), it is the breakpoint on 17q that has been interpreted as more important than the 15q changes in APL development [6]. Our patient represents a rare case of a variant translocation with an apparently intact chromosome 15 and most likely without any loss of genetic material from 17q; the breakpoint on #17 appears to be similar to a typical t(15;17). Furthermore, it is also the first case with APL and a rearrangement involving chromosomes 11 and 17.
106
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Figure 2 A partial karyotype from four marrow cells showing only abnormal chromosomes: t(7;12)(plS;p13) and t(11;17)(q13;q12).
The myeloperoxidase (MPO) gene has been mapped and localized to either 17q2224 [15], 17q12-q21 [16], or 17q22-23 [17]. Using in situ hybridization technique, two groups of investigators documented that MPO is translocated from chromosome 17 to 15q+ in five of eight studied patients with t(15;17) [15, 16]. Furthermore, rearrangements of MPO in two of four studied patients were described [16]. Based on these preliminary molecular studies and on rare variant chromosomal translocations, Weil et al. concluded that 15q+ is the critical recombinant chromosome [16]. Chromosomal localization of another gene, colony-stimulating factor (G-CSF), that promotes growth, differentiation and survival of neutrophilic granulocytes was recently mapped to the two close regions 17qll [18] and 17q11.2-21 [19]. Using in situ hybridization techniques, it has been shown that G-CSF remains on del(17q) and that the G-CSF coding sequence is not disturbed by t(15;17) [18, 19]. From these limited data it was concluded that t(15;17) apparently does not involve the G-CSF sequence, and again that 15q+ chromosome contains the critical function involved in APL pathogenesis. Six other genes have been localized in the region of APL translocations, and altogether seven of eight genes have been reported to be in the germ-line configuration in the typical t(15;17) [20]. Our patient had what appears to be an intact chromosome 15, and del(17q) could not be documented. Lack of involvement of chromosome 15 was documented in four
t(11;17) and t(7;12) in APL
107
patients [6-8]. Thus, either some of the changes on chromosome 15 are below cytogenetic resolution and, therefore, could not be detected, or other interpretations about APL pathogenesis are leasable in view of the fact that some patients with APL do not have involvement of c h r o m o s o m e 15. Our data are consistent with Yamada et al. that the recombinant c h r o m o s o m e 17 is a more critical chromosome and the position effect of one or more genes on 17q÷ (as in our patient) may be one of the explanations for the pathogenesis of APL [6]. But because both chromosomes 15 and 17 have been found intact in some cases of APL, either both play a role, or one or the other recombinant c h r o m o s o m e produces molecular events that can cause maturation arrest at the p r o m y e l o c y t e stage. This variant t(11;17) may be considered analogous either to the " m a s k e d " or complex Philadelphia (Ph) translocations without cytogenetic evidence of # 9 involvement in Ph-positive chronic myelogenous leukemia (CML) or to some variant translocations in Ph-negative CML without cytogenetic involvement of chromosomes 9 and 22, such as those recently described [21]. In some of these patients there is a formation of hybrid BCR-ABL gene and abnormal mRNA without cytogenetic evidence of the Ph chromosome [21, 22]. One may speculate that in a variant t(11;17) there might have been an exchange on a molecular level of genetic material with chromosome 15, even though chromosome 15 appears cytogenetically intact. The role of chromosome 15 in these rare variants remains speculative, and the juxtapositions of genes on both 15q and 17q in the pathogenesis of APL still needs further elucidation. A second abnormality observed in marrow cells of our patient was t(7;12) (p15;p12). This specific rearrangement has been d o c u m e n t e d in only one reported patient with acute n o n l y m p h o c y t i c leukemia (ANLL] [23]. Another similar reported case had a different breakpoint, at 7p13 [24]. Abnormality of c h r o m o s o m e 7, either in the form of del(7q), m o n o s o m y 7, or inv(Tq) have been frequently reported in APL [4, 18]. But in each case, the involvement of the long arms of chromosome 7 was documented. Therefore, involvements of 7p and 12p have been very rarely reported in ANLL. Two patients with t(7;12) as well as our patient received therapy prior to the c h r o m o s o m e analysis Thus, it may appear that t(7;12)(p15;p13) may be therapy related, rather than arising de novo, and may represent yet another, although rare, marker for treated patients. Therefore it is conceivable that t(7;12) was a secondary change to the primary t(11;17), which we suspect is associated with APL. In summary, a new variant translocation, t(11;17), was detected in relapsed marrow cells from a patient with APL. This translocation was probably a primary change in neoplastic cells. The other translocation, t(7;12), is most likely a secondary change and may represent a rare, n o n r a n d o m abnormality related to treatment. REFERENCES 1. Rowley JD, Golomb HM, Vardiman J, Fukuhara S, Dougherty C, Potter D (1977): Further evidence for a non-random chromosomal abnormality in acute promyelocytic leukemia. Int J Cancer 20:869-672. 2. Fourth International Workshop on Chromosomes in Leukemia, 1962. Chromosomes in acute promyelocytic leukemia (1964): Cancer Genet Cyiogenet 11:286-293. 3. Bloomfield CD, Trent JM, van Den Berghe (1967): Report of the committee on structural chromosome changes in neoplasia. Ninth International Workshop on Human Gene Mapping. (Paris Conference). Cytogenetics and Cell Genetics 46, Nos. 1-4, 344-369. 4. Larson RA, Kondo K, Vardiman JW, Butler AE, Golomb HM, Rowley JD (1984): Evidence for a 15:17 translocation in every patient with acute promyelocytic leukemia. Am J Med 76:627-641. 5. De Braekeleer M (1966): The occurrence of translocation (15;17) in acute promyelocytic leukemia: An update. Cancer Genet Cytogenet 23:275-277. 6. Yamada K, Sugimoto E, Amano M, Imamura Y, Kubota T, Matsumoto M (1963): Two cases
108
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7.
8. 9. 10. 11.
12.
13. 14.
15.
16.
17.
18.
19.
20.
21.
22. 23. 24.
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